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J. Fungi, Volume 4, Issue 3 (September 2018)

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Cover Story (view full-size image) A growing mycelium of Podospora anserina shows on the left a degenerating sector caused by the [...] Read more.
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Open AccessReview The Use of Galleria mellonella Larvae to Identify Novel Antimicrobial Agents against Fungal Species of Medical Interest
J. Fungi 2018, 4(3), 113; https://doi.org/10.3390/jof4030113
Received: 29 August 2018 / Revised: 14 September 2018 / Accepted: 15 September 2018 / Published: 19 September 2018
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Abstract
The immune system of insects and the innate immune response of mammals share many similarities and, as a result, insects may be used to assess the virulence of fungal pathogens and give results similar to those from mammals. Larvae of the greater wax
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The immune system of insects and the innate immune response of mammals share many similarities and, as a result, insects may be used to assess the virulence of fungal pathogens and give results similar to those from mammals. Larvae of the greater wax moth Galleria mellonella are widely used in this capacity and also for assessing the toxicity and in vivo efficacy of antifungal drugs. G. mellonella larvae are easy to use, inexpensive to purchase and house, and have none of the legal/ethical restrictions that are associated with use of mammals. Larvae may be inoculated by intra-hemocoel injection or by force-feeding. Larvae can be used to assess the in vivo toxicity of antifungal drugs using a variety of cellular, proteomic, and molecular techniques. Larvae have also been used to identify the optimum combinations of antifungal drugs for use in the treatment of recalcitrant fungal infections in mammals. The introduction of foreign material into the hemocoel of larvae can induce an immune priming effect which may operate independently with the activity of the antifungal drug. Procedures to identify this effect and limit its action are required. Full article
(This article belongs to the Special Issue Alternative Models for the Study of Fungal Host-Pathogen Interactions)
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Open AccessReview Tipping the Balance: C. albicans Adaptation in Polymicrobial Environments
J. Fungi 2018, 4(3), 112; https://doi.org/10.3390/jof4030112
Received: 29 August 2018 / Revised: 14 September 2018 / Accepted: 15 September 2018 / Published: 18 September 2018
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Abstract
Candida albicans is a pleiomorphic fungus which co-exists with commensal bacteria in mucosal and skin sites of mammalian hosts. It is also a major co-isolated organism from polymicrobial systemic infections, with high potential for morbidity or mortality in immunocompromised patients. Traditionally, resident mucosal
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Candida albicans is a pleiomorphic fungus which co-exists with commensal bacteria in mucosal and skin sites of mammalian hosts. It is also a major co-isolated organism from polymicrobial systemic infections, with high potential for morbidity or mortality in immunocompromised patients. Traditionally, resident mucosal bacteria have been thought to antagonize C. albicans in its ability to colonize or cause infection. However, recent investigations have revealed synergistic relationships with certain bacterial species that colonize the same mucosal sites with C. albicans. Such relationships broaden the research landscape in pathogenesis but also contribute to clinical challenges in the prevention or treatment of mucosal candidiasis. This review sheds light on interactions of C. albicans and mucosal bacteria, with special emphasis on the effects of the resident bacterial microbiota on C. albicans physiology as they relate to its adaptation in mucosal sites as a commensal colonizer or as a pathogenic organism. Full article
(This article belongs to the Special Issue Cell Adhesion in Fungal Life and Pathogenesis)
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Open AccessArticle Do Pentraxins Bind to Fungi in Invasive Human Gastrointestinal Candidiasis?
J. Fungi 2018, 4(3), 111; https://doi.org/10.3390/jof4030111
Received: 2 September 2018 / Accepted: 14 September 2018 / Published: 17 September 2018
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Abstract
Tissue from 13 autopsy cases with invasive gastrointestinal candidiasis was studied for the binding of the pentraxins, C-reactive protein (CRP), pentraxin 3 (PTX3), and serum amyloid P component (SAP) to fungal surfaces. Invasive candidal infection was demonstrated using a hematoxylin and eosin stain
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Tissue from 13 autopsy cases with invasive gastrointestinal candidiasis was studied for the binding of the pentraxins, C-reactive protein (CRP), pentraxin 3 (PTX3), and serum amyloid P component (SAP) to fungal surfaces. Invasive candidal infection was demonstrated using a hematoxylin and eosin stain and a Gomori methenamine silver stain (GMS). Immunohistochemistry was performed with CRP and PTX3 monoclonal antibodies and did not demonstrate CRP or PTX3 bound to fungi (0 of 13 cases), although CRP was extensively deposited on human tissue. A polyclonal antibody to SAP showed that SAP was bound to fungi in 12 of 13 cases. Although all three pentraxins have been reported to bind to fungi or bacteria, only SAP was bound to filamentous and yeast forms of Candida in human tissue, as detected by immunohistochemistry. SAP was abundantly present on fungi and may have affected the host innate immune response to the invading fungi. Full article
(This article belongs to the Special Issue Cell Adhesion in Fungal Life and Pathogenesis)
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Open AccessReview Susceptibility Testing of Fungi to Antifungal Drugs
J. Fungi 2018, 4(3), 110; https://doi.org/10.3390/jof4030110
Received: 15 July 2018 / Revised: 11 August 2018 / Accepted: 13 August 2018 / Published: 15 September 2018
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Abstract
Susceptibility testing of fungi against antifungal drugs commonly used for therapy is a key component of the care of patients with invasive fungal infections. Antifungal susceptibility testing (AFST) has progressed in recent decades to finally become standardized and available as both Clinical and
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Susceptibility testing of fungi against antifungal drugs commonly used for therapy is a key component of the care of patients with invasive fungal infections. Antifungal susceptibility testing (AFST) has progressed in recent decades to finally become standardized and available as both Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) reference methods and in commercial manual/automated phenotypic methods. In clinical practice, the Sensititre YeastOne and Etest methods are widely used for AFST, particularly for sterile site isolates of Candida. Nevertheless, AFST is moving toward new phenotypic methods, such as matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), that are capable of providing rapid, and potentially more actionable, results for the treating clinician. Our objective is to summarize updated data on phenotypic methods for AFST of Candida and Aspergillus species and to assess their significance in view of opposing, but emerging, molecular genotypic methods. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
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Open AccessArticle Characteristics of Invasive Fungal Infections among HIV Individuals from an Indigenous Origin in Mexico
J. Fungi 2018, 4(3), 109; https://doi.org/10.3390/jof4030109
Received: 17 August 2018 / Revised: 6 September 2018 / Accepted: 7 September 2018 / Published: 9 September 2018
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Abstract
In individuals with HIV/AIDS, 47% of the deaths are attributed to invasive fungal infections (IFIs), despite antiretroviral (ARV) therapy. This is a retrospective study carried out in the Hospital Regional de Alta Especialidad Oaxaca (HRAEO), southwest Mexico, where IFIs that occurred during 2016–2017
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In individuals with HIV/AIDS, 47% of the deaths are attributed to invasive fungal infections (IFIs), despite antiretroviral (ARV) therapy. This is a retrospective study carried out in the Hospital Regional de Alta Especialidad Oaxaca (HRAEO), southwest Mexico, where IFIs that occurred during 2016–2017 are described. A total of 55 individuals were included. Histoplasmosis (36%) and possible-IFIs in neutropenic fever (20%) were the most frequent cases, followed by cryptococcosis (14%). The HIV/AIDS subpopulation corresponded with 26 cases (47%), all from an indigenous origin. The incidence of IFIs among them was 24% (95% CI = 15–33%). The CD4+ T cells median was 35 cells/mL (IQR 12–58). Four cases (15%) of unmasking IRIS were identified, three of histoplasmosis and one coccidioidomycosis. Co-infections were found in 52% (12/23), and tuberculosis in 50% (6/12) was the most frequent. The mortality rate was 48%. The general characteristics of the HIV individuals who died were atypical pneumonia (70% vs. 9%, p = 0.01), acute kidney injury, (70% vs. 9%, p = 0.008) and ICU stay (80% vs. 9%, p = 0.002). In conclusion, IFIs are diagnosed in one out of four individuals with HIV/AIDS along with other complicated infectious conditions, leading to major complications and a high mortality rate. Full article
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Open AccessReview Standardization of G. mellonella Larvae to Provide Reliable and Reproducible Results in the Study of Fungal Pathogens
J. Fungi 2018, 4(3), 108; https://doi.org/10.3390/jof4030108
Received: 13 August 2018 / Revised: 31 August 2018 / Accepted: 5 September 2018 / Published: 6 September 2018
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Abstract
In the past decade, Galleria mellonella (wax moth) larvae have become widely used as a non-mammalian infection model. However, the full potential of this infection model has yet to be realised, limited by the variable quality of larvae used and the lack of
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In the past decade, Galleria mellonella (wax moth) larvae have become widely used as a non-mammalian infection model. However, the full potential of this infection model has yet to be realised, limited by the variable quality of larvae used and the lack of standardised procedures. Here, we review larvae suitable for research, protocols for dosing larvae, and methods for scoring illness in larvae infected with fungal pathogens. The development of standardised protocols for carrying out our experimental work will allow high throughput screens to be developed, changing the way in which we evaluate panels of mutants and strains. It will also enable the in vivo screening of potential antimicrobials at an earlier stage in the research and development cycle. Full article
(This article belongs to the Special Issue Alternative Models for the Study of Fungal Host-Pathogen Interactions)
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Open AccessReview Therapy and Antifungal Susceptibility Profile of Microsporum canis
J. Fungi 2018, 4(3), 107; https://doi.org/10.3390/jof4030107
Received: 30 July 2018 / Revised: 28 August 2018 / Accepted: 31 August 2018 / Published: 5 September 2018
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Abstract
Microsporum canis is a worldwide diffused zoophilic dermatophyte which causes clinical conditions often characterised by multifocal alopecia, scaling, and circular lesions in many animal species, including humans. A large variety of oral and topical antifungal protocols is available for treating M. canis infection.
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Microsporum canis is a worldwide diffused zoophilic dermatophyte which causes clinical conditions often characterised by multifocal alopecia, scaling, and circular lesions in many animal species, including humans. A large variety of oral and topical antifungal protocols is available for treating M. canis infection. However, the efficacy of these drugs and treatment protocols is variable, with treatment failure up to 40% of patients possibly due to resistance phenomena. The lack of standardised reference methods for evaluating the antifungal susceptibility of M. canis represents a major hindrance in assessing microbiological resistance in unresponsive clinical cases. Therefore, data about conventional therapy against M. canis and the protocols employed to test the antifungal activity of the most commonly employed drugs (i.e., azoles, polyenes, allylamines, and griseofulvin) have been summarised herein. This article focuses on technical parameters used for antifungal susceptibility tests, their effects on the minimum inhibitory concentration value, as well as their clinical implications. Full article
Open AccessArticle Sporothrix schenckii Cell Wall Proteins-Stimulated BMDCs Are Able to Induce a Th1-Prone Cytokine Profile In Vitro
J. Fungi 2018, 4(3), 106; https://doi.org/10.3390/jof4030106
Received: 4 August 2018 / Revised: 30 August 2018 / Accepted: 31 August 2018 / Published: 2 September 2018
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Abstract
Sporotrichosis is a subcutaneous mycosis affecting humans and other animals. The disease can be acquired by accidental inoculation of the fungus through the skin or through the respiratory system. Sporotrichosis can also be transmitted through bites or scratches by infected cats and more
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Sporotrichosis is a subcutaneous mycosis affecting humans and other animals. The disease can be acquired by accidental inoculation of the fungus through the skin or through the respiratory system. Sporotrichosis can also be transmitted through bites or scratches by infected cats and more rarely by other animals (zoonotic transmission). Conventional antifungal therapy is especially inefficient in immunocompromised patients, who tend to develop the most severe forms of the disease, thus prompting the search for alternative therapies. Given their antigen-presenting properties, dendritic cells (DCs) have been used in both prophylactic and therapeutic vaccination strategies. Hence, this study aims to assess the use of DCs as a prophylactic tool in sporotrichosis by evaluating the immune profile induced by Sporothrix schenckii cell wall proteins (SsCWP)-stimulated, bone-marrow-derived DCs (BMDCs). Mouse BMDCs were stimulated with SsCWP for 24 h and analyzed for the surface expression of costimulatory molecules and TLR-4, as well as for the secretion of proinflammatory cytokines and IL-10. Following that, activated BMDCs were cocultured with splenocytes for 72 h and had the same cytokines measured in the supernatant. SsCWP-stimulated BMDCs showed higher expression of CD80, CD86, and CD40, but not TLR-4, and higher secretion of IL-6, IL-17A, and TNF. On the other hand, higher levels of IFN-γ, IL-10, and IL-2 were found in the supernatants of the coculture as compared with the BMDCs alone; TNF secretion was almost completely abrogated, whereas IL-6 was only partially inhibited and IL-17A was unaffected. Our results thus suggest that SsCWP-stimulated BMDCs are able to induce a Th1-prone cytokine profile which is known to be protective against other fungal diseases. This result could lead to studies which evaluate the development of prophylactic and/or therapeutic DC-based tools against sporotrichosis. Full article
(This article belongs to the Special Issue Sporothrix and Sporotrichosis)
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Open AccessReview Fungal Resistance to Echinocandins and the MDR Phenomenon in Candida glabrata
J. Fungi 2018, 4(3), 105; https://doi.org/10.3390/jof4030105
Received: 16 August 2018 / Revised: 28 August 2018 / Accepted: 30 August 2018 / Published: 1 September 2018
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Abstract
Candida glabrata has thoroughly adapted to successfully colonize human mucosal membranes and survive in vivo pressures. prior to and during antifungal treatment. Out of all the medically relevant Candida species, C. glabrata has emerged as a leading cause of azole, echinocandin, and multidrug
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Candida glabrata has thoroughly adapted to successfully colonize human mucosal membranes and survive in vivo pressures. prior to and during antifungal treatment. Out of all the medically relevant Candida species, C. glabrata has emerged as a leading cause of azole, echinocandin, and multidrug (MDR: azole + echinocandin) adaptive resistance. Neither mechanism of resistance is intrinsic to C. glabrata, since stable genetic resistance depends on mutation of drug target genes, FKS1 and FKS2 (echinocandin resistance), and a transcription factor, PDR1, which controls expression of major drug transporters, such as CDR1 (azole resistance). However, another hallmark of C. glabrata is the ability to withstand drug pressure both in vitro and in vivo prior to stable “genetic escape”. Additionally, these resistance events can arise within individual patients, which underscores the importance of understanding how this fungus is adapting to its environment and to drug exposure in vivo. Here, we explore the evolution of echinocandin resistance as a multistep model that includes general cell stress, drug adaptation (tolerance), and genetic escape. The extensive genetic diversity reported in C. glabrata is highlighted. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
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Open AccessEditorial Special Issue: Fungal Endophytes in Plants
J. Fungi 2018, 4(3), 104; https://doi.org/10.3390/jof4030104
Received: 24 August 2018 / Revised: 25 August 2018 / Accepted: 28 August 2018 / Published: 1 September 2018
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(This article belongs to the Special Issue Fungal Endophytes in Plants) Printed Edition available
Open AccessArticle Itraconazole, Voriconazole, and Posaconazole CLSI MIC Distributions for Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates
J. Fungi 2018, 4(3), 103; https://doi.org/10.3390/jof4030103
Received: 31 July 2018 / Revised: 22 August 2018 / Accepted: 23 August 2018 / Published: 29 August 2018
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Abstract
Azole resistance in Aspergillus fumigatus is most frequently conferred by mutations in the cyp51A gene encoding 14α-sterol demethylases. TR34/L98H and TR46/Y121F/T289A are the two most common mutations associated with environmental resistance selection. We studied the minimal inhibitory concentration (MIC)
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Azole resistance in Aspergillus fumigatus is most frequently conferred by mutations in the cyp51A gene encoding 14α-sterol demethylases. TR34/L98H and TR46/Y121F/T289A are the two most common mutations associated with environmental resistance selection. We studied the minimal inhibitory concentration (MIC) distribution of clinical A. fumigatus isolates to characterize the Clinical and Laboratory Standards Institute (CLSI) susceptibility profiles of isolates with the wild-type (WT) cyp51A genotype, and isolates with the TR34/L98H and TR46/Y121F/T289A cyp51A mutations. Susceptibility testing was performed according to CLSI M38-A2. The MICs of 363 A. fumigatus isolates were used in this study. Based on the CLSI epidemiological cut-off values (ECVs), 141 isolates were phenotypically non-WT and 222 isolates had a phenotypically WT susceptibility. All isolates with the TR34/L98H mutation had an itraconazole MIC > 1 mg/L which is above the CLSI ECV. Eighty-six of 89 (97%) isolates with the TR34/L98H mutation had voriconazole and posaconazole MICs above the CLSI ECV, i.e., MICs of 1 and 0.25 mg/L, respectively. The isolates with a TR46/Y121F/T289A mutation showed a different phenotype. All 37 isolates with a TR46/Y121F/T289A mutation had a voriconazole MIC above the CLSI ECV, while 28/37 (76%) isolates had an itraconazole MIC > 1 mg/L. Interestingly, only 13 of 37 (35%) isolates had a posaconazole MIC > 0.25 mg/L. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
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Open AccessArticle A Solvent-Free Approach for Converting Cellulose Waste into Volatile Organic Compounds with Endophytic Fungi
J. Fungi 2018, 4(3), 102; https://doi.org/10.3390/jof4030102
Received: 25 June 2018 / Revised: 20 August 2018 / Accepted: 23 August 2018 / Published: 26 August 2018
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Abstract
Simple sugars produced from a solvent-free mechanocatalytic degradation of cellulose were evaluated for suitability as a growth medium carbon source for fungi that produce volatile organic compounds. An endophytic Hypoxylon sp. (CI-4) known to produce volatiles having potential value as fuels was initially
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Simple sugars produced from a solvent-free mechanocatalytic degradation of cellulose were evaluated for suitability as a growth medium carbon source for fungi that produce volatile organic compounds. An endophytic Hypoxylon sp. (CI-4) known to produce volatiles having potential value as fuels was initially evaluated. The growth was obtained on a medium containing the degraded cellulose as the sole carbon source, and the volatile compounds produced were largely the same as those produced from a conventional dextrose/starch diet. A second Hypoxylon sp. (BS15) was also characterized and shown to be phylogenetically divergent from any other named species. The degraded cellulose medium supported the growth of BS15, and approximately the same quantity of the volatile compounds was produced as from conventional diets. Although the major products from BS15 grown on the degraded cellulose were identical to those from dextrose, the minor products differed. Neither CI-4 or BS15 exhibited growth on cellulose that had not been degraded. The extraction of volatiles from the growth media was achieved using solid-phase extraction in order to reduce the solvent waste and more efficiently retain compounds having low vapor pressures. A comparison to more conventional liquid–liquid extraction demonstrated that, for CI-4, both methods gave similar results. The solid-phase extraction of BS15 retained a significantly larger variety of the volatile compounds than did the liquid–liquid extraction. These advances position the coupling of solvent-free cellulose conversion and endophyte metabolism as a viable strategy for the production of important hydrocarbons. Full article
(This article belongs to the Special Issue Fungal Endophytes in Plants) Printed Edition available
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Open AccessReview Mangrove-Associated Fungi: A Novel Source of Potential Anticancer Compounds
J. Fungi 2018, 4(3), 101; https://doi.org/10.3390/jof4030101
Received: 16 July 2018 / Revised: 14 August 2018 / Accepted: 21 August 2018 / Published: 24 August 2018
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Abstract
Cancer is the second leading cause of death worldwide, and the number of cases is increasing alarmingly every year. Current research focuses on the development of novel chemotherapeutic drugs derived from natural as well as synthetic sources. The abundance and diversity in natural
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Cancer is the second leading cause of death worldwide, and the number of cases is increasing alarmingly every year. Current research focuses on the development of novel chemotherapeutic drugs derived from natural as well as synthetic sources. The abundance and diversity in natural resources offer tremendous potential for the discovery of novel molecules with unique mechanisms for cancer therapy. Mangrove-derived fungi are rich source of novel metabolites, comprising novel structure classes with diverse biological activities. Across the globe, coastal areas are primarily dominated by mangrove forests, which offer an intensely complex environment and species that mostly remain unexplored. In recent years, many structurally diverse compounds with unique skeletons have been identified from mangrove fungi and evaluated for their antiproliferative properties. These compounds may serve as lead molecules for the development of new anticancer drugs. Mangrove endophytes can be modulated using epigenetic means or culture optimization methods to improve the yield or to produce various similar analogs. The present review provides an insight into the bioactive metabolites from mangrove endophytes reported during the period from 2012 to 2018 (up to April, 2018) along with their cytotoxic properties, focusing on their chemical structures and mode of action, as indicated in the literature. Full article
(This article belongs to the Special Issue Fungal Endophytes in Plants) Printed Edition available
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Open AccessReview Therapy of Skin, Hair and Nail Fungal Infections
J. Fungi 2018, 4(3), 99; https://doi.org/10.3390/jof4030099
Received: 25 June 2018 / Revised: 10 August 2018 / Accepted: 10 August 2018 / Published: 20 August 2018
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Abstract
Treatment of superficial fungal infections has come a long way. This has, in part, been through the development and evaluation of new drugs. However, utilising new strategies, such as identifying variation between different species in responsiveness, e.g., in tinea capitis, as well as
[...] Read more.
Treatment of superficial fungal infections has come a long way. This has, in part, been through the development and evaluation of new drugs. However, utilising new strategies, such as identifying variation between different species in responsiveness, e.g., in tinea capitis, as well as seeking better ways of ensuring adequate concentrations of drug in the skin or nail, and combining different treatment methods, have played equally important roles in ensuring steady improvements in the results of treatment. Yet there are still areas where we look for improvement, such as better remission and cure rates in fungal nail disease, and the development of effective community treatment programmes to address endemic scalp ringworm. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
Open AccessReview Immunity and Treatment of Sporotrichosis
J. Fungi 2018, 4(3), 100; https://doi.org/10.3390/jof4030100
Received: 18 July 2018 / Revised: 18 August 2018 / Accepted: 19 August 2018 / Published: 20 August 2018
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Abstract
Species of the Sporothrix complex are the etiological agents of sporotrichosis, an important subcutaneous mycosis with several clinical forms and an increasing incidence around the world that affects humans and other mammals. The immunological mechanisms involved in the prevention and control of this
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Species of the Sporothrix complex are the etiological agents of sporotrichosis, an important subcutaneous mycosis with several clinical forms and an increasing incidence around the world that affects humans and other mammals. The immunological mechanisms involved in the prevention and control of this mycosis are not entirely understood. Many reports have suggested that cell-mediated immunity has an essential role in the development of the disease, being the primary response controlling it, while only recent data supports that the humoral response is essential for the appropriate control. This mycosis is a challenge for diagnosis since the culture and isolation of the organism are time-consuming and complicated; reasons that have led to the study of fungus antigenic molecules capable of generating a detectable humoral response. The treatment for this disease includes the use of several antifungal drugs like itraconazole, amphotericin B, caspofungin, fluconazole, and the combination between them among others such as the extract of Vismia guianensis. Full article
(This article belongs to the Special Issue Sporothrix and Sporotrichosis)
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Open AccessReview Treatment of Aspergillosis
J. Fungi 2018, 4(3), 98; https://doi.org/10.3390/jof4030098
Received: 24 July 2018 / Revised: 12 August 2018 / Accepted: 15 August 2018 / Published: 19 August 2018
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Abstract
Infections caused by Aspergillus spp. remain associated with high morbidity and mortality. While mold-active antifungal prophylaxis has led to a decrease of occurrence of invasive aspergillosis (IA) in those patients most at risk for infection, breakthrough IA does occur and remains difficult to
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Infections caused by Aspergillus spp. remain associated with high morbidity and mortality. While mold-active antifungal prophylaxis has led to a decrease of occurrence of invasive aspergillosis (IA) in those patients most at risk for infection, breakthrough IA does occur and remains difficult to diagnose due to low sensitivities of mycological tests for IA. IA is also increasingly observed in other non-neutropenic patient groups, where clinical presentation is atypical and diagnosis remains challenging. Early and targeted systemic antifungal treatment remains the most important predictive factor for a successful outcome in immunocompromised individuals. Recent guidelines recommend voriconazole and/or isavuconazole for the primary treatment of IA, with liposomal amphotericin B being the first alternative, and posaconazole, as well as echinocandins, primarily recommended for salvage treatment. Few studies have evaluated treatment options for chronic pulmonary aspergillosis (CPA), where long-term oral itraconazole or voriconazole remain the treatment of choice. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
Open AccessReview Treatment of Invasive Candidiasis: A Narrative Review
J. Fungi 2018, 4(3), 97; https://doi.org/10.3390/jof4030097
Received: 25 July 2018 / Revised: 8 August 2018 / Accepted: 12 August 2018 / Published: 16 August 2018
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Abstract
Invasive candidiasis occurs frequently in hospitalized patients, and is associated with high mortality rates due to delays in recognition and initiation of appropriate antifungals. Management of invasive candidiasis must take into account multiple host, pathogen, and drug-related factors, including the site of infection,
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Invasive candidiasis occurs frequently in hospitalized patients, and is associated with high mortality rates due to delays in recognition and initiation of appropriate antifungals. Management of invasive candidiasis must take into account multiple host, pathogen, and drug-related factors, including the site of infection, host immune status, severity of sepsis, resistance and tolerance to antifungal agents, biofilm formation, and pharmacokinetic/pharmacodynamic considerations. Recent treatment directives have been shaped by the widespread introduction of echinocandins, highly potent and safe antifungals, into clinical use, as well as important changes in drug susceptibility patterns and the emergence of known and novel drug-resistant Candida species. Advances in molecular diagnostics have the potential to guide early targeted treatment of high-risk patients. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
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Open AccessArticle Oryzines A & B, Maleidride Congeners from Aspergillus oryzae and Their Putative Biosynthesis
J. Fungi 2018, 4(3), 96; https://doi.org/10.3390/jof4030096
Received: 19 July 2018 / Revised: 8 August 2018 / Accepted: 10 August 2018 / Published: 13 August 2018
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Abstract
Aspergillus oryzae is traditionally used in East Asia for the production of food and brewing. In addition, it has been developed into a suitable host for the heterologous expression of natural product biosynthetic genes and gene clusters, enabling the functional analysis of the
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Aspergillus oryzae is traditionally used in East Asia for the production of food and brewing. In addition, it has been developed into a suitable host for the heterologous expression of natural product biosynthetic genes and gene clusters, enabling the functional analysis of the encoded enzymes. A. oryzae shares a 99.5% genome homology with Aspergillus flavus, but their secondary metabolomes differ significantly and various compounds unique to A. oryzae have been reported. While using A. oryzae as a host for heterologous expression experiments we discovered two new metabolites in extracts of A. oryzae M-2-3 with an unusual maleidride backbone, which were named oryzine A and B. Their structures were elucidated by high resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR) analysis. Their structural relationships with known maleidrides implied involvement of a citrate synthase (CS) and a polyketide (PKS) or fatty acid synthase (FAS) in their biosynthesis. Analysis of the A. oryzae genome revealed a single putative biosynthetic gene cluster (BGC) consistent with the hypothetical biosynthesis of the oryzines. These findings increase knowledge of the chemical potential of A. oryzae and are the first attempt to link a novel product of this fungus with genomic data. Full article
(This article belongs to the Special Issue Fungal Polyketides and Other Secondary Metabolites)
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Open AccessArticle Ecological Determinants of Sporotrichosis Etiological Agents
J. Fungi 2018, 4(3), 95; https://doi.org/10.3390/jof4030095
Received: 29 June 2018 / Revised: 4 August 2018 / Accepted: 10 August 2018 / Published: 12 August 2018
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Abstract
Ecological determinants of sporotrichosis etiological agents remain poorly understood. For this reason, we performed explorations using local climate estimates to determine the temperature and humidity ranges of the environment where clinically relevant Sporothrix species occur and to identify what plant species are associated
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Ecological determinants of sporotrichosis etiological agents remain poorly understood. For this reason, we performed explorations using local climate estimates to determine the temperature and humidity ranges of the environment where clinically relevant Sporothrix species occur and to identify what plant species are associated with them, using data collected from the published literature. We performed a literature search to identify all publications on environmental isolations of medically relevant species of Sporothrix in the PubMed, SCOPUS, and EMBASE databases. All those studies were included in the analysis where medically relevant species of Sporothrix have been isolated from soil samples, and described a specific geographical location that could be precisely georeferenced. We approximated temperature and humidity from local climate estimates, integrating geospatial data, temperature, and water vapor pressure from regions or provinces where medically relevant species of Sporothrix have been isolated from soil. Sporothrix spp. were more commonly isolated from soil of different regions or provinces of 16 countries. Most environmental isolates were identified as S. schenckii, whereas S. pallida, S. brasiliensis, S. globosa, and S. mexicana were rare. We estimate that medically relevant Sporothrix spp. grow in the soil at temperatures of 6.6 °C to 28.84 °C and 37.5% to 99.06% relative humidity. These findings indicate that sporotrichosis etiological agents grow in soil in ecological niches from soil with wide ranges of temperature and humidity, but they are also associated with a variety of plants, flowers, woody debris, reed leaves, corn stalks, leaves, and wood crumbs, potentially facilitating its establishment and proliferation in the environment. Full article
(This article belongs to the Special Issue Sporothrix and Sporotrichosis)
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Open AccessArticle Management of Invasive Fungal Infections in Adult Patients with Hematological Malignancies in Greece during the Financial Crisis: Challenges and Recommendations
J. Fungi 2018, 4(3), 94; https://doi.org/10.3390/jof4030094
Received: 17 July 2018 / Revised: 4 August 2018 / Accepted: 8 August 2018 / Published: 9 August 2018
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Abstract
There are concerns that the financial crisis in Greece negatively affected the management of invasive fungal infections (IFIs) among patients with hematological malignancies (HM). A working group (WG) was formed to explore the situation and make recommendations. A questionnaire was created and distributed
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There are concerns that the financial crisis in Greece negatively affected the management of invasive fungal infections (IFIs) among patients with hematological malignancies (HM). A working group (WG) was formed to explore the situation and make recommendations. A questionnaire was created and distributed to physicians caring for patients with HM, to gather information in a standardized manner on prescribing physicians, patient characteristics, availability of diagnostics, antifungal treatment practices and the conditions and particularities of Greek hospitals. A total of 141 physicians from 36 hematology units and laboratories located in 26 Greek hospitals participated. Regarding hospitalization conditions, only 56% reported that their patients were treated in isolated single or double bed rooms, 22% reported availability of HEPA filters, 47% reported construction works in progress, and an alarming 18% reported the presence of birds on open windows. Regarding diagnosis, only 31% reported availability of biomarkers for diagnosis of IFIs, 76% reported that CT scans were performed in a timely fashion, 42% reported prompt availability of broncho-alveolar lavage, and only 6% availability of therapeutic drug monitoring. Of concern, 26% of the responders reported non-availability of some antifungals. In conclusion, significant challenges exist for the optimal management of IFIs in patients with HM in Greece. Full article
Open AccessArticle Impact of Fungal MAPK Pathway Targets on the Cell Wall
J. Fungi 2018, 4(3), 93; https://doi.org/10.3390/jof4030093
Received: 2 July 2018 / Revised: 31 July 2018 / Accepted: 2 August 2018 / Published: 9 August 2018
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Abstract
The fungal cell wall is an extracellular organelle that provides structure and protection to cells. The cell wall also influences the interactions of cells with each other and surfaces. The cell wall can be reorganized in response to changing environmental conditions and different
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The fungal cell wall is an extracellular organelle that provides structure and protection to cells. The cell wall also influences the interactions of cells with each other and surfaces. The cell wall can be reorganized in response to changing environmental conditions and different types of stress. Signaling pathways control the remodeling of the cell wall through target proteins that are in many cases not well defined. The Mitogen Activated Protein Kinase pathway that controls filamentous growth in yeast (fMAPK) was required for normal growth in media containing the cell wall perturbing agent Calcofluor White (CFW). A mass spectrometry (MASS-SPEC) approach and analysis of expression profiling data identified cell wall proteins and modifying enzymes whose levels were influenced by the fMAPK pathway. These include Flo11p, Flo10p, Tip1p, Pry2p and the mannosyltransferase, Och1p. Cells lacking Flo11p or Och1p were sensitive to CFW. The identification of cell wall proteins controlled by a MAPK pathway may provide insights into how signaling pathways regulate the cell wall. Full article
(This article belongs to the Special Issue Cell Adhesion in Fungal Life and Pathogenesis)
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Open AccessArticle Monitoring Fungal Burden and Viability of Sporothrix spp. in Skin Lesions of Cats for Predicting Antifungal Treatment Response
J. Fungi 2018, 4(3), 92; https://doi.org/10.3390/jof4030092
Received: 29 June 2018 / Revised: 2 August 2018 / Accepted: 3 August 2018 / Published: 7 August 2018
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Abstract
Skin lesions in feline sporotrichosis usually present a high fungal burden, making cats an important source of infection. This study evaluated the fungal burden and isolation in skin lesions of feline sporotrichosis during treatment with itraconazole (ITZ), combined with or without potassium iodide
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Skin lesions in feline sporotrichosis usually present a high fungal burden, making cats an important source of infection. This study evaluated the fungal burden and isolation in skin lesions of feline sporotrichosis during treatment with itraconazole (ITZ), combined with or without potassium iodide (KI). Treatment-naïve cats with culture-confirmed sporotrichosis and presenting skin ulcers were treated for up to 40 weeks with oral ITZ alone (n = 74) or combined with KI (n = 56). These cats were submitted to monthly sampling of the same lesion for mycological culture and cytopathology until healing of lesion or up to twelve weeks. The fungal burden was expressed as the mean yeast cell count in three microscopic fields from imprint smears. The fungal burden before treatment was significantly higher in cats in which the lesion persisted and in cases of treatment failure when using ITZ alone. After twelve weeks, the median fungal burden decreased to zero in both treatment protocols, suggesting a potential decrease in the risk of transmission of Sporothrix spp. from cats. These findings encourage the early treatment of feline sporotrichosis as a control measure. Moreover, the fungal burden in feline sporotrichosis lesions can be a prognostic indicator and a parameter for choosing appropriate therapeutic regimen. Full article
(This article belongs to the Special Issue Sporothrix and Sporotrichosis)
Open AccessEditorial Special Issue: Fungal Cell Wall
J. Fungi 2018, 4(3), 91; https://doi.org/10.3390/jof4030091
Received: 27 July 2018 / Accepted: 31 July 2018 / Published: 4 August 2018
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(This article belongs to the Special Issue Fungal Cell Wall)
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Open AccessReview Therapy of Mucormycosis
J. Fungi 2018, 4(3), 90; https://doi.org/10.3390/jof4030090
Received: 15 July 2018 / Revised: 28 July 2018 / Accepted: 30 July 2018 / Published: 31 July 2018
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Abstract
Despite the recent introduction of mold-active agents (posaconazole and isavuconazole), in addition to amphotericin B products, to our armamentarium against mucormycosis, many uncertainties remain for the management of this uncommon opportunistic infection, as there are no data from prospective randomized clinical trials to
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Despite the recent introduction of mold-active agents (posaconazole and isavuconazole), in addition to amphotericin B products, to our armamentarium against mucormycosis, many uncertainties remain for the management of this uncommon opportunistic infection, as there are no data from prospective randomized clinical trials to guide therapy. In this mini-review, we present the current status of treatment options. In view of the heterogeneity of the disease (different types of affected hosts, sites of infection, and infecting Mucorales), mucormycosis management requires an individualized management plan that takes into account the net state of immunosuppression of the host, including comorbidities, certainty of diagnosis, site of infection, and antifungal pharmacological properties. Full article
(This article belongs to the Special Issue Treatments for Fungal Infections)
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Open AccessReview Immunopathogenesis of Human Sporotrichosis: What We Already Know
J. Fungi 2018, 4(3), 89; https://doi.org/10.3390/jof4030089
Received: 30 June 2018 / Revised: 26 July 2018 / Accepted: 27 July 2018 / Published: 31 July 2018
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Abstract
Sporotrichosis is a subacute/chronic mycosis caused by dimorphic fungus of the genus Sporothrix. This mycosis may affect both human and domestic animals and in the last few years, the geographic dispersion and increase of sporotrichosis worldwide has been observed. The occurrence of cases
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Sporotrichosis is a subacute/chronic mycosis caused by dimorphic fungus of the genus Sporothrix. This mycosis may affect both human and domestic animals and in the last few years, the geographic dispersion and increase of sporotrichosis worldwide has been observed. The occurrence of cases related to scratching/bites of domestic felines have increased, characterizing the disease as predominantly a zoonosis. In humans, sporotrichosis mainly involves the cutaneous tegument of infected patients, but other tissues may also present the infection. The main forms of clinical presentation are lymphocutanous sporotrichosis (LC) and fixed sporotrichosis (F). Although less common, mucosal, cutaneous disseminated, and extracutaneous forms have also been described. Multiple factors from the fungus and host can play a role in driving the clinical evolution of sporotrichosis to benign or severe disease. In this review, we discuss the immunopathological aspects involved in human sporotrichosis. Putting together the two branches of knowledge—host immune response and fungal evading mechanisms—we may perceive new possibilities in understanding the fungus–host interaction in order to be in a position to go further in the control of sporotrichosis. Full article
(This article belongs to the Special Issue Sporothrix and Sporotrichosis)
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Open AccessReview Cryptococcal Traits Mediating Adherence to Biotic and Abiotic Surfaces
J. Fungi 2018, 4(3), 88; https://doi.org/10.3390/jof4030088
Received: 1 July 2018 / Revised: 25 July 2018 / Accepted: 27 July 2018 / Published: 29 July 2018
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Abstract
Several species in the genus Cryptococcus are facultative intracellular pathogens capable of causing disease associated with high mortality and morbidity in humans. These fungi interact with other organisms in the soil, and these interactions may contribute to the development of adaptation mechanisms that
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Several species in the genus Cryptococcus are facultative intracellular pathogens capable of causing disease associated with high mortality and morbidity in humans. These fungi interact with other organisms in the soil, and these interactions may contribute to the development of adaptation mechanisms that function in virulence by promoting fungal survival in animal hosts. Fungal adhesion molecules, also known as adhesins, have been classically considered as cell-surface or secreted proteins that play critical roles in microbial pathogenesis or in biofilm formation as structural components. Pathogenic Cryptococcus spp. differ from other pathogenic yeasts in having a polysaccharide capsule that covers the cell wall surface and precludes interactions of those structures with host cell receptors. Hence, pathogenic Cryptococcus spp. use unconventional tools for surface attachment. In this essay, we review the unique traits and mechanisms favoring adhesion of Cryptococcus spp. to biotic and abiotic surfaces. Knowledge of the traits that mediate adherence could be exploited in the development of therapeutic, biomedical, and/or industrial products. Full article
(This article belongs to the Special Issue Cell Adhesion in Fungal Life and Pathogenesis)
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Open AccessReview Challenges and Opportunities in the Management of Onychomycosis
J. Fungi 2018, 4(3), 87; https://doi.org/10.3390/jof4030087
Received: 5 July 2018 / Revised: 19 July 2018 / Accepted: 23 July 2018 / Published: 24 July 2018
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Abstract
Onychomycosis is an increasingly common fungal nail infection, chiefly caused by dermatophyte fungi. The disease is notoriously difficult to treat due to the deep-seated nature of fungi within the nail plate, prolonged treatment requirements, poor patient adherence and frequent recurrences. Given the poor
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Onychomycosis is an increasingly common fungal nail infection, chiefly caused by dermatophyte fungi. The disease is notoriously difficult to treat due to the deep-seated nature of fungi within the nail plate, prolonged treatment requirements, poor patient adherence and frequent recurrences. Given the poor efficacy of currently available topical and systemic therapies, there is a renewed interest in exploring alternative treatment modalities for onychomycosis. Natural therapies, physical treatments and various combination therapies have all shown potential for the management of onychomycosis, though research on many of these methods is still in preliminary stages. Further large, well-designed, randomised controlled trials are necessary to confirm the efficacy of these novel treatments in order to make formal recommendations regarding their use in the management of onychomycosis. Full article
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Open AccessArticle Molecular Identification, Antifungal Susceptibility, and Geographic Origin of Clinical Strains of Sporothrix schenckii Complex in Mexico
J. Fungi 2018, 4(3), 86; https://doi.org/10.3390/jof4030086
Received: 14 June 2018 / Revised: 16 July 2018 / Accepted: 18 July 2018 / Published: 20 July 2018
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Abstract
Sporotrichosis is a subcutaneous mycosis caused by Sporothrix schenckii complex. The disease has been reported worldwide. However, the incidence of the etiological agent varies in its geographic distribution. We studied 39 clinical isolates of Sporothrix schenckii from diverse regions in Mexico, collected from
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Sporotrichosis is a subcutaneous mycosis caused by Sporothrix schenckii complex. The disease has been reported worldwide. However, the incidence of the etiological agent varies in its geographic distribution. We studied 39 clinical isolates of Sporothrix schenckii from diverse regions in Mexico, collected from 1998 to 2016. Molecular identification was performed by sequence analysis of the partial calmodulin gene. In vitro antifungal susceptibility to amphotericin B (AMB), itraconazole (ITC), voriconazole (VRC), posaconazole (PSC), fluconazole (FLC), terbinafine (TRB), caspofungin (CSF), anidulafungin (ANF), and micafungin (MCF) was evaluated. Thirty-eight isolates of S. schenckii complex were divided into five supported clades in a phylogenetic tree. The predominant clinical form was lymphocutaneous (92.3%), fixed cutaneous (5.1%), and disseminated (2.5%). Terbinafine exhibited the best in vitro antifungal activity, while fluconazole was ineffective against Sporothrix schenckii complex. Our results showed diverse geographic distribution of clinical isolates in eight states; definitive identification was done by CAL gen PCR-sequencing. In Mexico, S. schenckii is considered to be an etiological agent of human sporotrichosis cases, and lymphocutaneous is the most prevalent form of the disease. This study revealed four clades of S. schenckiisensu stricto by phylogenetic analysis. Furthermore, we report one case of S. globosa isolated from human origin from the North of Mexico. Full article
(This article belongs to the Special Issue Sporothrix and Sporotrichosis)
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Open AccessArticle PaPro1 and IDC4, Two Genes Controlling Stationary Phase, Sexual Development and Cell Degeneration in Podospora anserina
J. Fungi 2018, 4(3), 85; https://doi.org/10.3390/jof4030085
Received: 11 June 2018 / Revised: 28 June 2018 / Accepted: 10 July 2018 / Published: 11 July 2018
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Abstract
Filamentous fungi frequently undergo bistable phenotypic switches. Crippled Growth of Podospora anserina is one such bistable switch, which seems to rely upon the mis-activation of a self-regulated PaMpk1 MAP kinase regulatory pathway. Here, we identify two new partners of this pathway: PaPro1, a
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Filamentous fungi frequently undergo bistable phenotypic switches. Crippled Growth of Podospora anserina is one such bistable switch, which seems to rely upon the mis-activation of a self-regulated PaMpk1 MAP kinase regulatory pathway. Here, we identify two new partners of this pathway: PaPro1, a transcription factor orthologous to Sordaria macrospora pro1 and Neurospora crassa ADV-1, and IDC4, a protein with an AIM24 domain. Both PaPro1 and IDC4 regulate stationary phase features, as described for the other actors of the PaMpk1 signaling pathway. However, PaPro1 is also involved in the control of fertilization by activating the transcription of the HMG8 and the mating type transcription factors, as well as the sexual pheromones and receptor genes. The roles of two components of the STRIPAK complex were also investigated by inactivating their encoding genes: PaPro22 and PaPro45. The mutants of these genes were found to have the same phenotypes as PaPro1 and IDC4 mutants as well as additional phenotypes including slow growth, abnormally shaped hyphae, pigment accumulation and blockage of the zygotic tissue development, indicating that the STRIPAK complex regulates, in addition to the PaMpk1 one, other pathways in P. anserina. Overall, the mutants of these four genes confirm the model by which Crippled Growth is due to the abnormal activation of the PaMpk1 MAP kinase cascade. Full article
(This article belongs to the Special Issue Regulation of Fungal Morphogenesis and Gene Expression)
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Open AccessArticle Inter-Specimen Imbalance of Mitochondrial Gene Copy Numbers Predicts Clustering of Pneumocystis jirovecii Isolates in Distinct Subgroups
J. Fungi 2018, 4(3), 84; https://doi.org/10.3390/jof4030084
Received: 7 June 2018 / Revised: 4 July 2018 / Accepted: 9 July 2018 / Published: 10 July 2018
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Abstract
The molecular detection of Pneumocystis jirovecii is an important therapy-relevant tool in microbiological diagnostics. However, the quantification of this pathogen in the past has revealed discordant results depending on the target gene. As the clinical variety of P. jirovecii infections ranges between life-threatening
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The molecular detection of Pneumocystis jirovecii is an important therapy-relevant tool in microbiological diagnostics. However, the quantification of this pathogen in the past has revealed discordant results depending on the target gene. As the clinical variety of P. jirovecii infections ranges between life-threatening infections and symptom-free colonization, the question arises if qPCRs are reliable tools for quantitative diagnostics of P. jirovecii. P. jirovecii positive BALs were quantitatively tested for the copy numbers of one mitochondrial (COX-1) and two nuclear single-copy genes (KEX1 and DHPS) compared to the mitochondrial large subunit (mtLSU) by qPCR. Independent of the overall mtLSU copy number P. jirovecii clustered into distinct groups based on the ratio patterns of the respective qPCRs. This study, which compared different mitochondrial to nuclear gene ratio patterns of independent patients, shows that the mtLSU gene represents a highly sensitive qPCR tool for the detection of P. jirovecii, but does not display a reliable target for absolute quantification. Full article
(This article belongs to the Special Issue Molecular Diagnostics of Fungal Infections)
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